Over the years, the community of Framingham has changed. In the early 1990s, the need to establish a new study reflecting the increasing diversity of the community was recognized and in 1994 a new group of participants was enrolled. They are the Omni Cohort of the Framingham Heart Study. The original Omni cohort consisted of 506 men and women of African-American, Hispanic, Asian, Indian, Pacific Islander and Native American origins, who at the time of enrollment were residents of Framingham and the surrounding towns. The original Omni Cohort continues to be examined and followed.

In order to parallel the original Omni Cohort and to represent an ethnically diverse group at least 10% of the size of the Gen III, enrollment of a second generation of Omni participants started in 2003 and ended in July 2005. In this phase the Study was expanded to include those who would like to participate but were unrelated to the original Omni cohort. When this phase ended 410 Omni second generation participants had been seen.